U.S. patent application number 13/307474 was filed with the patent office on 2013-05-30 for polymeric drug-delivery material, method for manufacturing thereof and method for delivery of a drug-delivery composition.
The applicant listed for this patent is Scott Hampton, Jorg Kriwanek, Sonja Ludwig, Andreas Reiff, Andreas Voigt. Invention is credited to Scott Hampton, Jorg Kriwanek, Sonja Ludwig, Andreas Reiff, Andreas Voigt.
Application Number | 20130136774 13/307474 |
Document ID | / |
Family ID | 47278823 |
Filed Date | 2013-05-30 |
United States Patent
Application |
20130136774 |
Kind Code |
A1 |
Voigt; Andreas ; et
al. |
May 30, 2013 |
POLYMERIC DRUG-DELIVERY MATERIAL, METHOD FOR MANUFACTURING THEREOF
AND METHOD FOR DELIVERY OF A DRUG-DELIVERY COMPOSITION
Abstract
A method for manufacturing a drug-delivery composition includes
providing at least one pharmaceutically active compound, a dry
powder comprising at least a polymer, and an aqueous solution. The
dry powder, the pharmaceutically active compound and the aqueous
solution are mixed to form a paste-like or semi-solid drug-delivery
composition, wherein the aqueous solution is added in an amount of
less than or equal to twice the total dry mass of the dry
powder.
Inventors: |
Voigt; Andreas; (Berlin,
DE) ; Kriwanek; Jorg; (Berlin, DE) ; Hampton;
Scott; (Cumming, GA) ; Reiff; Andreas; (San
Marino, CA) ; Ludwig; Sonja; (Berlin, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Voigt; Andreas
Kriwanek; Jorg
Hampton; Scott
Reiff; Andreas
Ludwig; Sonja |
Berlin
Berlin
Cumming
San Marino
Berlin |
GA
CA |
DE
DE
US
US
DE |
|
|
Family ID: |
47278823 |
Appl. No.: |
13/307474 |
Filed: |
November 30, 2011 |
Current U.S.
Class: |
424/400 ;
424/130.1; 424/133.1; 424/141.1; 424/93.1; 424/93.6; 424/94.1;
514/1.1; 514/44R; 514/7.6; 514/9.7 |
Current CPC
Class: |
A61K 47/36 20130101;
A61K 47/42 20130101; A61K 9/06 20130101; A61K 9/5036 20130101; A61K
47/38 20130101; C07K 16/00 20130101 |
Class at
Publication: |
424/400 ;
424/130.1; 514/1.1; 514/44.R; 424/133.1; 424/141.1; 424/93.1;
424/94.1; 514/7.6; 514/9.7; 424/93.6 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 31/7105 20060101 A61K031/7105; A61K 35/12
20060101 A61K035/12; A61K 31/711 20060101 A61K031/711; A61K 38/18
20060101 A61K038/18; A61K 38/22 20060101 A61K038/22; A61K 35/76
20060101 A61K035/76; A61K 9/14 20060101 A61K009/14; A61K 38/02
20060101 A61K038/02; A61K 38/43 20060101 A61K038/43 |
Claims
1. A method for manufacturing a drug-delivery composition,
comprising: providing at least one pharmaceutically active
compound, a dry powder comprising at least a polymer, and an
aqueous solution; mixing the dry powder, the pharmaceutically
active compound and the aqueous solution to form a paste-like or
semi-solid drug-delivery composition, wherein the aqueous solution
is added in an amount less than or equal to twice the total dry
mass of the dry powder.
2. The method according to claim 1, wherein the added amount of the
aqueous solution is less than or equal to the total dry mass of the
dry powder mixture.
3. The method according to claim 1, further comprising: providing
the pharmaceutically active compound as dry pharmaceutically active
compound powder; and homogeneously mixing the dry polymer powder
with the dry pharmaceutically active compound to prepare a dry
powder mixture before adding the aqueous solution.
4. The method according to claim 3, wherein the dry
pharmaceutically active compound powder comprises at least the
pharmaceutically active compound and at least one excipient
selected from the group consisting of monosaccharides,
disaccharides, oligosaccharides, polysaccharides like hyaluronic
acid, pectin, gum arabic and other gums, albumin, chitosan,
collagen, collagen-n-hydroxysuccinimide, fibrin, fibrinogen,
gelatin, globulin, polyaminoacids, polyurethane comprising amino
acids, prolamin, protein-based polymers, copolymers and derivatives
thereof, and mixtures thereof.
5. The method according to claim 1, wherein the aqueous solution is
added step-wise to form the drug-delivery composition.
6. The method according to claim 1, wherein the formation of the
paste-like or semi-solid drug-delivery composition includes
repeated cycles of pressing and folding in an algorithmic manner of
the mixture of the dry powder, the pharmaceutically active compound
and the aqueous solution.
7. The method according to claim 6, wherein the aqueous solution is
added step-wise during pressing and folding.
8. The method according to claim 6, wherein the pressing applies a
pressure of not more than 10.sup.6 Nm.sup.-2.
9. The method according to claim 1, wherein the dry powder is mixed
at least with a portion of the aqueous solution before the dry
pharmaceutically active compound is added.
10. The method according to claim 1, wherein the pharmaceutically
active compound is solved in the aqueous solution before being
mixed with the dry powder.
11. The method according to claim 1, further comprising: mixing the
dry powder and the aqueous solution to form a paste-like or
semi-solid mass; and adding the pharmaceutically active compound to
the paste-like or semi-solid mass to form the paste-like or
semi-solid drug-delivery composition.
12. The method according to claim 11, wherein the pharmaceutical
active compound is added as solution.
13. The method according to claim 1, wherein the pharmaceutical
active compound is provided as powder comprising particles in a
range from about 100 nm to about 50 .mu.m.
14. The method according to claim 1, wherein the polymer is a
hydrophilic polymer that swells when mixed with the aqueous
solution.
15. The method according to claim 1, wherein the polymer has a
molecular weight of at least 10 kDa.
16. The method according to claim 1, wherein the pharmaceutically
active compound is selected from a group consisting of
immunoglobulins, fragments or fractions of immunoglobulins,
synthetic substance mimicking immunoglobulins or fragments or
fractions thereof, peptides having a molecular mass equal to or
higher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids
(DNA), plasmids, peptide nucleic acids (PNA), steroids, and
corticosteroids.
17. The method according to claim 1, wherein the pharmaceutically
active compound is selected from the group consisting of:
immunoglobulins, fragments or fractions of immunoglobulins,
synthetic substance mimicking immunoglobulins or synthetic,
semisynthetic or biosynthetic fragments or fractions thereof,
chimeric, humanized or human monoclonal antibodies, Fab fragments,
fusion proteins or receptor antagonists (e.g., anti-TNF alpha,
Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,
anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.g
JAK1,3 and SYK inhibitors) peptides having a molecular mass equal
to or higher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic
acids (DNA), plasmids, peptide nucleic acids (PNA), steroids,
corticosteroids, an adrenocorticostatic, an antibiotic, an
antidepressant, an antimycotic, a [beta]-adrenolytic, an androgen
or antiandrogen, an antianemic, an anabolic, an anaesthetic, an
analeptic, an antiallergic, an antiarrhythmic, an
antiarterosclerotic, an antibiotic, an antifibrinolytic, an
anticonvulsive, an antiinflammatory drug an anticholinergic, an
antihistaminic, an antihypertensive, an antihypotensive, an
anticoagulant, an antiseptic, an antihemorrhagic, an
antimyasthenic, an antiphlogistic, an antipyretic, a beta-receptor
antagonist, a calcium channel antagonist, a cell, a cell
differentiation factor, a chemokine, a chemotherapeutic, a
coenzyme, a cytotoxic agent, a prodrug of a cytotoxic agent, a
cytostatic, an enzyme and its synthetic or biosynthetic analogue, a
glucocorticoid, a growth factor, a haemostatic, a hormone and its
synthetic or biosynthetic analogue, an immunosuppressant, an
immunostimulant, a mitogen, a physiological or pharmacological
inhibitor of mitogens, a mineralcorticoid, a muscle relaxant, a
narcotic, a neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
18. The method according to claim 1, further comprising: forming
the drug-delivery composition into an applicable form.
19. The method according to claim 1, wherein the polymer is
selected from the group consisting of, polyvinyl alcohol (PVA),
polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), gelatin,
collagen, starch, cellulose, chitosan, albumin, fibrin, fibrinogen,
pectin, gum arabic and other gums, carrageenan, hyaluronic acid,
polyethyleneimine, protamin, therapeutic proteins and peptides,
nucleic acids, ribonucleic acids and derivatives thereof.
20. A drug-delivery composition, comprising: a paste-like or
semi-solid mixture comprising at least a polymer, a
pharmaceutically active compound, and an aqueous solution, wherein
the total amount of the aqueous solution in the paste-like or
semi-solid mixture is less than or equal to twice the total dry
mass of the mixture.
21. The drug-delivery composition according to claim 20, wherein
the total amount of the aqueous solution is less than or equal to
the total dry mass of the mixture.
22. The drug-delivery composition according to claim 20, wherein
the aqueous solution comprises water and electrolyte.
23. The drug-delivery composition according to claim 20, wherein
the paste-like or semi-solid mixture has a modulus of elasticity at
least of 10.sup.-4Nmm.sup.-2.
24. The drug-delivery composition according to claim 20, wherein
the paste-like or semi-solid mixture has a viscosity of at least
100 mPas.
25. The drug-delivery composition according to claim 20, wherein
the pharmaceutically active compound is selected from the group
consisting of immunoglobulins, fragments or fractions of
immunoglobulins, synthetic substance mimicking immunoglobulins or
fragments or fractions thereof, therapeutic proteins, peptides
having a molecular mass equal to or higher than 3 kDa, ribonucleic
acids (RNA), desoxyribonucleic acids (DNA), plasmids, peptide
nucleic acids (PNA), steroids, and corticosteroids.
26. The drug-delivery composition according to claim 20, wherein
the pharmaceutically active compound is selected from the group
consisting of immunoglobulins, fragments or fractions of
immunoglobulins, synthetic substance mimicking immunoglobulins or
synthetic, semisynthetic or biosynthetic fragments or fractions
thereof, chimeric, humanized or human monoclonal antibodies, Fab
fragments, fusion proteins or receptor antagonists (e.g., anti
TNF-alpha, Interleukin-1, Interleukin-6 etc.), antiangiogenic
compounds (e.g., anti-VEGF, anti-PDGF etc.), intracellular
signaling inhibitors (e.g JAK1,3 and SYK inhibitors) peptides
having a molecular mass equal to or higher than 3 kDa, ribonucleic
acids (RNA), desoxyribonucleic acids (DNA), plasmids, peptide
nucleic acids (PNA), steroids, corticosteroids, an
adrenocorticostatic, an antibiotic, an antidepressant, an
antimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, an
antianemic, an anabolic, an anaesthetic, an analeptic, an
antiallergic, an antiarrhythmic, an antiarterosclerotic, an
antibiotic, an antifibrinolytic, an anticonvulsive, an
antiinflammatory drug an anticholinergic, an antihistaminic, an
antihypertensive, an antihypotensive, an anticoagulant, an
antiseptic, an antihemorrhagic, an antimyasthenic, an
antiphlogistic, an antipyretic, a beta-receptor antagonist, a
calcium channel antagonist, a cell, a cell differentiation factor,
a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, a
prodrug of a cytotoxic agent, a cytostatic, an enzyme and its
synthetic or biosynthetic analogue, a glucocorticoid, a growth
factor, a haemostatic, a hormone and its synthetic or biosynthetic
analogue, an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
27. A method for delivery of a drug-delivery composition,
comprising: providing a drug-delivery composition comprising a
paste-like or semi-solid mixture comprising at least a polymer, a
pharmaceutically active compound, and an aqueous solution, wherein
the total amount of the aqueous solution in the paste-like or
semi-solid mixture is less than or equal to twice the total dry
mass of the mixture; applying the drug-delivery composition into a
human or animal body.
28. The method of claim 27, wherein applying the mixture into the
human or animal body comprises at least one of: implanting or
injecting the mixture into a human or animal body; intraocular
injecting the mixture into a human, or animal body; subcutaneous
injecting the mixture into a human, or animal body; intramuscular
injecting the mixture into a human, or animal body; intraperitoneal
injecting the mixture into a human, or animal body; intravenously
injecting the mixture into a human, or animal body; administration
of the mixture into a human or animal body by inhalation or
intranasal application; intravenously injecting the mixture into a
human or animal body; and administration of the mixture into a
human or animal body by inhalation or intranasal application.
Description
FIELD OF THE INVENTION
[0001] The present invention belongs to the field of controlled
drug release, particularly to methods for manufacturing
drug-delivery compositions including pharmaceutically active
substances or compounds, and to the controlled delivery thereof
into living organisms and tissues for therapeutic purposes.
BACKGROUND OF THE INVENTION
[0002] Most therapeutic dosage forms include mixtures of one or
more active pharmaceutical ingredients (APIs) with additional
components referred to as excipients. APIs are substances which
exert a pharmacological effect on a living tissue or organism,
whether used for prevention, treatment, or cure of a disease. APIs
can occur naturally, be produced synthetically or by recombinant
methods, or any combination of these approaches.
[0003] Numerous methods have been devised for delivering APIs into
living organisms, each with more or less success. Traditional oral
therapeutic dosage forms include both solids (tablets, capsules,
pills, etc.) and liquids (solutions, suspensions, emulsions, etc.).
Parenteral dosage forms include solids and liquids as well as
aerosols (administered by inhalers, etc.), injectables
(administered with syringes, micro-needle arrays, etc.), topicals
(foams, ointments, etc.), and suppositories, among other dosage
forms. Although these dosage forms might be effective in delivering
low molecular weight APIs, each of these methods suffers from one
or more drawbacks, including the lack of bioavailability as well as
the inability to completely control either the spatial or the
temporal component of the API's distribution when it comes to high
molecular weight APIs. These drawbacks are especially challenging
for administering biotherapeutics, i.e. pharmaceutically active
peptides (e.g. growth factors), proteins (e.g. enzymes,
antibodies), oligonucleotides (e.g. RNA, DNA, PNA), hormones and
other natural substances or similar synthetic substances, since
many of these pharmacologically active biomolecules are at least
partially broken down by the digestive tract or in the blood system
and are subsequently delivered in suboptimal dosing to the target
site.
[0004] Therefore, there is an ongoing need for improved
drug-delivery methods in life sciences, including but not limited
to human and veterinary medicine. One important goal for any new
drug-delivery method is to deliver the desired therapeutic agent(s)
to a specific place in the body over a specific and controllable
period of time, i.e. controlling the delivery of one or more
substances to specific organs and tissues in the body with control
of the location and release over time. Methods for accomplishing
this localized and time controlled delivery are known as
controlled-release drug-delivery methods. Delivering APIs to
specific organs and tissues in the body offers several potential
advantages, including increased patient compliance, extending
activity, lowering the required dose, minimizing systemic side
effects, and permitting the use of more potent therapeutics. In
some cases, controlled-release drug-delivery methods can even allow
the administration of therapeutic agents that would otherwise be
too toxic or ineffective for use.
[0005] There are five broad types of solid dosage forms for
controlled-delivery oral administration: reservoir and matrix
diffusive dissolution, osmotic, ion-exchange resins, and prodrugs.
For parenterals, most of the above solid dosage forms are available
as well as injections (intravenous, intramuscular, etc.),
transdermal systems, and implants. Numerous products have been
developed for both oral and parenteral administration, including
depots, pumps, micro- and nano-particles.
[0006] The incorporation of APIs into polymer matrices acting as a
core reservoir is one approach for controlling their delivery.
Contemporary approaches for formulating such drug-delivery systems
are dependent on technological capabilities as well as the specific
requirements of the application. For sustained delivery systems
there are two main structural approaches: the controlled release by
diffusion through a barrier such as shell, coat, or membrane, and
the controlled release by the intrinsic local binding strength of
the API(s) to the core or to other ingredients in the core
reservoir.
[0007] Another strategy for controlled delivery of therapeutic
agents, especially for delivering biotherapeutics, is their
incorporation into polymeric micro- and nano-particles either by
covalent or cleavable linkage or by trapping or adsorption inside
porous network structures. Various particle architectures can be
designed, for instance core/shell structures. Typically one or more
APIs are contained either in the core, in the shell, or in both
components. Their concentration can vary throughout the respective
component in order to modify their release pattern. Although
polymeric nano-spheres can be effective in the controlled delivery
of APIs, they also suffer from several disadvantages. For example,
their small size can allow them to diffuse in and out of the target
tissue. The use of intravenous nano-particles may also be limited
due to rapid clearance by the reticuloendothelial system or
macrophages Notwithstanding, polymeric micro-spheres remain an
important delivery vehicle.
[0008] In view of the above, there is a need for improving
drug-delivery methods and compositions.
SUMMARY OF THE INVENTION
[0009] According to an embodiment, a method for manufacturing a
drug-delivery composition is provided. The method includes
providing at least one pharmaceutically active compound, a dry
powder including at least a polymer, and an aqueous solution; and
mixing the dry powder, the pharmaceutically active compound and the
aqueous solution to form a paste-like or semi-solid drug-delivery
composition, wherein the aqueous solution is added in a total
amount of less than or equal to twice the total dry mass of the dry
powder.
[0010] According to an embodiment, a drug-delivery composition is
provided, which includes a paste-like or semi-solid mixture
including at least a polymer, a pharmaceutically active compound,
and an aqueous solution, wherein the total amount of the aqueous
solution in the paste-like or semi-solid mixture is less than or
equal to twice the total dry mass of the mixture.
[0011] According to an embodiment, a method for delivering a
drug-delivery composition is provided. The method includes
providing a drug-delivery composition including a paste-like or
semi-solid mixture having at least a polymer, a pharmaceutically
active compound, and an aqueous solution, wherein the total amount
of the aqueous solution in the paste-like or semi-solid mixture is
less than or equal to twice the total dry mass of the mixture; and
applying the drug-delivery composition into a human or animal
body.
[0012] Those skilled in the art will recognize additional features
and advantages upon reading the following detailed description, and
upon viewing the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The accompanying drawings are included to provide a further
understanding of embodiments and are incorporated in and constitute
a part of this specification. The drawings illustrate embodiments
and together with the description serve to explain principles of
embodiments. Other embodiments and many of the intended advantages
of embodiments will be readily appreciated, as they become better
understood by reference to the following detailed description. The
elements of the drawings are not necessarily to scale relative to
each other. Like reference numerals designate corresponding similar
parts.
[0014] FIG. 1 illustrates processing steps of a manufacturing
method according to an embodiment.
[0015] FIG. 2 illustrates processing steps of a manufacturing
method according to an embodiment.
[0016] FIG. 3 shows a photograph of the stable gelatin body
obtained according to an embodiment and according to the procedure
of FIG. 2.
[0017] FIGS. 4a and 4b show photographs of water-based formulations
of gelatin-water mixtures according to the procedure illustrated in
FIG. 2 and described by the experiment of FIG. 3.
[0018] FIG. 5 demonstrates a series of eight photographs of
dry-route formulations (prepared as described in FIG. 2) combining
carboxymethylcellulose (CMC) with chitosan.
[0019] FIG. 6 presents a series of six photographs of dry-route
formulations according to FIG. 2 combining carboxymethylcellulose
with chitosan beginning with (a) acetic acid and (b) plant oil as
wetting agents.
[0020] FIG. 7 presents antibody release curves from drug-delivery
compositions prepared according to several examples illustrating
embodiments.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The following language and descriptions of certain preferred
embodiments of the present invention are provided to further an
understanding of the principles of the present invention. However,
it will be understood that no limitations of the present invention
are intended, and that further alterations, modifications, and
applications of the principles of the present invention are also
included.
[0022] According to an embodiment a drug-delivery composition is
manufactured by providing at least one pharmaceutically active
compound, a dry powder including at least a polymer, and an aqueous
solution. The dry powder, the pharmaceutically active compound and
the aqueous solution are then mixed to form a paste-like or
semi-solid drug-delivery composition, wherein the aqueous solution
is added in an amount less than or equal to twice the total dry
mass of the dry powder. The pharmaceutically active compound is
referred to hereinafter as active pharmaceutical ingredient
(API).
[0023] For the purpose of this specification, the term "mixing"
intends to describe a mechanical working or a mechanical treatment
of the components. For example, mixing can be in the sense of
carrying out repeated cycles of pressing and folding or comparable
process steps which lead to an intense compression and mixing of
the provided water-deficient or quasi-dry compositions and
mixtures. Mixing includes, according to an embodiment, pressing and
folding of a water-deficient composition including API(s),
excipients and an aqueous solution such as water. An embodiment
also includes cold extruding of the composition.
[0024] The drug-delivery composition includes polymeric delivery
materials formed from dry mixtures by a process which can include,
according to an embodiment, intimate mixing of a dry powder mixture
and then continuously wetting and mixing the powder in a controlled
manner, without intermittent drying steps, to achieve an
API-containing semi-solid material, possessing superior
controlled-delivery properties. It is believed, that the step-wise
addition of only small amounts of the aqueous solution such as
water, a composite liquid, or a solvent with sustained mixing of
the components (e.g. algorithmic pressing-folding cycles) allows
for specific molecular interactions by solute shielding layers at
interfaces, especially in the vicinity of functional groups and
structural elements of the involved macromolecules, which would be
otherwise suppressed by self organization or self assembly in free
solution or suspension. Such interactions relate to intra-molecular
interactions of both excipients and involved APIs but also to
intermolecular interactions of both excipients and APIs and of
excipients with APIs.
[0025] By slowly hydrating and mixing the solid mixture, it is
believed that APIs come into better and more-controlled contact
with the excipients doing the same with each other. This results in
the onset of different interaction mechanisms, which would
otherwise not be triggered. The suggested method is especially
suitable for formulating biological compounds. Biopolymer-like
proteins, peptides, poly- and oligonucleotides are particularly
sensitive to changes in their environment and may lose their
specific activity more readily than small-molecule APIs. Synthetic
APIs and excipients mimicking biomacromolecules may carry both
anionic and cationic groups in the relevant medium or may possess
different functional groups in variable density on a molecular
backbone. These molecules, i.e. biopolymers and polyampholytes are
known to have different configurations depending on the molecular
environment, i.e. distinct folding patterns, tertiary and
quaternary structures. Since a certain activity may be closely
related to a certain spatial configuration, these molecules are apt
to altered release characteristics when formulated according to the
suggested method. Therefore, the approach described herein is
believed to have a minimal impact on the natural conformation of
the APIs and is thus especially advantageous for the stable
formulation of biotherapeutics by controlled release.
[0026] The suggested approach combines the benefit of initial
thorough dry-mixing with the controlled-release advantages of
polymeric micro-spheres but does not suffer from the disadvantages
of any of these formulations when applied alone.
[0027] The matrix formed by the polymer is typically a hydrophilic
matrix but can also include a small amount of hydrophobic
substances.
[0028] The resulting polymeric drug-delivery materials can be
subsequently transferred into the final dosage form either directly
or after an optional, later step of forming semi-solid particles,
bodies or micro-particles of desired shape, size and size
distribution by means of colloid forming techniques and other
technological procedures. Remarkably, any solute or dispersant in
excess of 200% by weight of the APIs and involved excipients as
well as any intermittent drying or evaporating of solute or
dispersant from the semi-solid material, may be avoided in order to
reach and to maintain the specific properties of the formed
API-excipient complex. According to an embodiment, no additional
solute is added during formation of the drug-delivery composition
so that the composition does not transform into a more liquid form.
According to an embodiment, the drug-delivery composition is not
dried but kept as paste. This ensures that the specific release
characteristics can be maintained.
[0029] The compositions formed by the methods described herein can
maintain the drug-releasing properties for a prolonged time such as
weeks and months. The APIs remain protected in the paste-like or
semi-solid mixture so that their bioavailability can be maintained.
If desired, additional barrier layers can be formed around the
paste-like or semi-solid mixture.
[0030] The suggested method is different from other approaches in
that the paste-like or semi-solid composition is formed by addition
of a solution to a dry powder of a polymer, which forms the matrix
of the composition into which the API is distributed and mixed.
According to an embodiment, the paste-like or semi-solid
composition is formed by kneading, as an example of algorithmic
pressing-folding cycles.
[0031] According to an embodiment, the API is provided as dry
pharmaceutically active compound powder. The dry polymer powder is
homogeneously mixed with the dry pharmaceutically active compound
to prepare a dry pre-powder mixture before the aqueous solution is
added. The solution can either be added step-wise or continuously.
Intensive mechanical working such as kneading may be needed for
mixing the dry pre-mixture with the slowly or step-wise added
solution to form a paste. It is believed that the intense
mechanical interaction with the slow or step-wise addition of the
solution results in the specific molecular interaction between the
polymer matrix itself and also between the polymer matrix and the
API and optional excipients as described above.
[0032] According to an embodiment, the added amount of the aqueous
solution is less than or equal to twice the total dry mass of the
dry powder mixture. According to a further embodiment, the added
amount of the aqueous solution is less than or equal to the total
dry mass of the dry powder mixture.
[0033] The processing can include repeated pressing and folding of
the mixture of the dry powder, the pharmaceutically active compound
and the aqueous solution to form the paste-like or semi-solid
drug-delivery composition. For example, a small amount of the
solution is added to the polymer powder or the pre-mixtures of
polymer and API. The mechanical processing may start with pressing
to bring the mass into a more flat shape and then folding the mass,
for example by a blade or other suitable means. The folded mass is
then pressed again. By repeating these procedures a distribution of
the solution and APIs throughout the powder mass can be achieved.
During this mechanical processing, more solution is added so that
more and more of the powder mass is "wetted" to form a paste. The
addition of the API to the treated system can occur during all
phases of the preparation process, and, according to an embodiment,
at a late stage after forming an established excipient matrix
system. It guarantees a minimum mechanical/mixture influence on the
APIs.
[0034] According to an embodiment, the mechanical processing of the
mass can also include other processes such as rolling.
[0035] The force acting on the mass may be limited to avoid
excessive mechanical impact that might affect the API. According to
an embodiment, a pressure of not more than 10.sup.6 Nm.sup.-2 is
applied to the mass. According to further embodiments, a pressure
of not more than 5.times.10.sup.5 Nm.sup.-2 is applied to the
mass.
[0036] According to an embodiment, the pharmaceutically active
compound (API) is dissolved in the aqueous solution before being
mixed with the dry polymer powder. The API is not provided as dry
component but as component dissolved in the solution. However,
since the solution is added in a limited amount, it is believed
that the aforementioned specific molecular interactions also take
place.
[0037] According to an embodiment, the dry powder and the aqueous
solution are mixed to form a paste-like or semi-solid mass and then
the pharmaceutically active compound (API) is added to the
paste-like or semi-solid mass to form the paste-like or semi-solid
drug-delivery composition. The API can either be added in dry or
liquid form such as dissolved in a solution. When adding in liquid
form, the amount of liquid added should be taken into account for
the amount of solution added to the dry powder to keep the
drug-delivery composition in paste-like or semi-solid form. The
solution added to the dry powder and the solution in which the API
is dissolved can be the same or can be different.
[0038] According to an embodiment, the API can be provided in
particulate form such as micro-particles or nano-particles.
Suitable particle size ranges are from about 100 nm to about 50
.mu.m, particularly from about 500 nm to about 30 .mu.m, and more
particularly from about 1 .mu.m to about 10 .mu.m.
[0039] According to an embodiment, the polymer for the hydrophilic
matrix is a hydrophilic polymer that swells when mixed with the
aqueous solution. Suitable polymers are polyvinyl alcohol (PVA),
polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), gelatin,
collagen, alginate, starch, cellulose, chitosan,
carboxymethylcellulose, cellulose derivatives, pectin, gum arabic,
carrageenan, hyaluronic acid, albumin, fibrin, fibrinogen,
synthetic polyelectrolytes, polyethylenimine, acacia gum, xanthan
gum, agar agar, polyvinylalcohol, borax, polyacrylic acids
including derivatives, protaminsulfate, casein, and derivatives
thereof. According to an embodiment, inorganic polymers such as
clay and silica can also be used for the hydrophilic matrix.
According to an embodiment, the polymer has a molecular weight of
at least 10 kDa. Furthermore, polyampholytes can be used as a
polymer component. According to an embodiment, a polymer from the
group of biopolymers is used. According to an embodiment, a polymer
from the group of hydrogel forming substances such as gelatin is
used. According to an embodiment, a polymer from the group of
polyelectrolyte complex forming substances is used. Such substances
typically include two components of opposite charge selected from
two polyelectrolytes of opposite charge and a polyelectrolyte and a
small ion of opposite charge such as alginate and calcium.
According to an embodiment, a polymer from the group of
polyampholytes is used. According to an embodiment, a polymer from
the group of inorganic gel forming substances is used.
[0040] It is assumed that the method as described herein leads to
very specific molecular interactions, which define the release
characteristics of the polymeric drug-delivery composition.
Different to macromolecules in free solution, the amount of the
added solution in the method as described herein is so small that
the resulting composition cannot be regarded as free solution.
Typically, the amount of solution is only equal to, or even only a
fraction of, the initial dry powder mass, so that the formulation
route is expected to operate along a deficient amount of dissolving
water supporting the intimate contact of all possible
intermolecular interaction spots. This early, intimate, and
controlled contact of the matrix excipients with each other and
with APIs establishes various stabilizing and function-improving or
-conserving intra- and intermolecular interactions to obtain a more
controlled procedure. The method as described herein may employ a
ratio of the mass fraction of aqueous solution to the dry matrix
components between 0.1 and 2, preferably between 0.3 and 1.2, and
most preferably between 0.5 and 1. Consequently, the components
cannot be considered to be completely dissolved or dispersed, but
should instead be thought of as binding partners for which the
other system components compete. Thus, the medium has to be
considered as a partner at the same level as the API and the
macromolecular excipients. Also, the release medium conditions have
to be taken into account in order to obtain a quantitative estimate
of the release kinetics. Ultimately, the energy difference with
respect to an ideal thermodynamic equilibrium and the presence of
activation barriers determine the release conditions of the API
from the formulated structure. This is especially relevant because
a lower free energy of active binding and lower activation barriers
will favor faster release kinetics.
[0041] In the novel approach as described herein, the controlled
addition of liquid (mainly aqueous solutions or water or composite
liquid or solvent) transforms the preparation into a paste- or
dough-like consistency, which is appropriate for the production of
slow release compositions. The processes according to one
embodiment include mixing of all ingredients in dry form in a first
step followed by wetting these mixtures and adding liquid media in
a controlled manner to transform the wetted mixtures into
paste-like or semi-solid consistency. Thus, the interactions of the
formulation/fabrication procedures are controlled throughout the
method.
[0042] As described herein, composite polymeric delivery materials
can be formed by maintaining control over strength and sequence of
the different API-excipient interactions from the beginning of the
process. Thus, even during the initial dry-powder mixing, the
interactions occur under essentially non-wetted conditions. These
interactions are switched on or off or modified by the step-wise
addition of limited amounts of liquid media such as water, protic
solvents (e.g. acetic acid) or aqueous solutions. This approach
also helps to minimize the use of excipients and water or solvent,
since these formulation routes are processed under minimal
water/solvent conditions. Thus, one aspect of the method described
herein is the ability to start with maximum concentration of the
API(s). For example, a gelatin gel is stabilized by more or less
hydrophobic spots distributed at a given concentration throughout
the self-organized gel. The spot concentration depends on the
dissolved gelatin concentration. The proposed novel approach
increases the gelatin stabilizing hydrophobic spot concentration or
equivalently the material concentration per spot far above this
equilibrium value by the addition of both, low amounts of water and
mechanical treatment overcoming the repulsive barriers for forming
the high concentration stabilizing spots throughout the gel/water
mass. Surprisingly, this new configuration demonstrates a
tremendous stability (meta-stability) created by a driven process
as opposed to self-organization or self-assembly.
[0043] Independent of the selected route, the precise control of
all interactions between the APIs and excipients is desired in
order to achieve successful formulation, even if excipients form
membranes that have to be penetrated by the APIs. Thus, the methods
as described herein starts with maximum concentrations of both the
APIs and the excipients according to an embodiment and subsequently
adapt the conditions during the process of mixture, structuring,
manufacturing, and polymeric delivery material formation up to the
essential concentrations in the final delivery forms.
[0044] According to an embodiment, APIs can be small molecules,
peptides, proteins, therapeutic proteins, antibodies, antigens,
enzymes, receptor ligands, nucleotides or nucleotide analogs,
oligonucleotides and oligonucleotide analogs, genes or gene-like
species, viruses, virus-like particles, sugars or polysaccharides
or their analogs, or any other physical composition such as living
organelles, cells, or tissue constituents. According to an
embodiment. Excipients can include almost any member of these same
classes of species. They often act as buffer, filler, binder,
osmotic agent, lubricant, or fulfill similar functions.
Polyampholytes are multiply-charged polymers which bear both
anionic and cationic groups in the relevant medium, e.g. in an
aqueous solution. The various classes and types of APIs,
excipients, polymers, and polyampholytes are familiar to those
skilled in the art of drug delivery.
[0045] According to an embodiment, the excipient can be, for
example, a sugar such as monosaccharides, disaccharides,
oligosaccharides, polysaccharides, or albumin, chitosan, collagen,
collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin,
globulin, polyaminoacids, polyurethane comprising amino acids,
prolamin, protein-based polymers, copolymers and derivatives
thereof, and mixtures thereof.
[0046] According to an embodiment, the pharmaceutically active
compound can be one or more of immunoglobulins, fragments or
fractions of immunoglobulins, synthetic substance mimicking
immunoglobulins or synthetic, semisynthetic or biosynthetic
fragments or fractions thereof, chimeric, humanized or human
monoclonal antibodies, Fab fragments, fusion proteins or receptor
antagonists (e.g., anti-TNF alpha, Interleukin-1, Interleukin-6
etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),
intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),
peptides having a molecular mass equal to or higher than 3 kDa,
ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,
peptide nucleic acids (PNA), steroids, corticosteroids, an
adrenocorticostatic, an antibiotic, an antidepressant, an
antimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, an
antianemic, an anabolic, an anaesthetic, an analeptic, an
antiallergic, an antiarrhythmic, an antiarterosclerotic, an
antibiotic, an antifibrinolytic, an anticonvulsive, an
antiinflammatory drug, an anticholinergic, an antihistaminic, an
antihypertensive, an antihypotensive, an anticoagulant, an
antiseptic, an antihemorrhagic, an antimyasthenic, an
antiphlogistic, an antipyretic, a beta-receptor antagonist, a
calcium channel antagonist, a cell, a cell differentiation factor,
a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, a
prodrug of a cytotoxic agent, a cytostatic, an enzyme and its
synthetic or biosynthetic analogue, a glucocorticoid, a growth
factor, a haemostatic, a hormone and its synthetic or biosynthetic
analogue, an immunosuppressant, an immunostimulant, a mitogen, a
physiological or pharmacological inhibitor of mitogens, a
mineralcorticoid, a muscle relaxant, a narcotic, a
neurotransmitter, a precursor of a neurotransmitter, an
oligonucleotide, a peptide, a (para)-sympathicomimetic, a
(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, a
vasoconstrictor, a vasodilatator, a vector, a virus, a virus-like
particle, a virustatic, a wound-healing substance, and combinations
thereof.
[0047] According to an embodiment, the drug-delivery composition
can be brought into an implantable form to form an implantable
drug-delivery formulation with controlled-release kinetics. The
bringing into an implantable form can include addition of
biodegradable or bioerodible polymers. The polymer matrix itself
according to the novel proposed approach can also be comprised of
biodegradable or bioerodible polymers. Furthermore, a micro-porous
membrane made from ethylene/vinyl acetate copolymer or other
materials for ocular use can be formed around the paste-like or
semi-solid mixture. Further options include use of biodegradable
polymers for subcutaneous and intramuscular injection, bioerodible
polysaccharides, hydrogels. The implantable drug-delivery
formulation can be activated by osmotic pressure, or any other
mechanism tested in the past, like vapor pressure or magnetism.
[0048] The approach described herein distinguishes from oral
formulations such as tablets, caplets, and pills in that a
paste-like or semi-solid composition is prepared. Commonly known
administered formulations may include powder mixtures. However,
they are merely compressed or coated compacts produced from
thoroughly mixed amorphous or crystalline powders.
[0049] The present invention encompasses not only the use of pure
aqueous media but can comprise also minor amounts of plant oils or
any other pharmaceutically acceptable solvents or their mixtures.
The method and composition described herein can use any substance
which can exert a therapeutic effect, including small molecules,
synthetic or biological macromolecules such as peptides, proteins,
oligonucleotides, carbohydrates, and others familiar to one skilled
in the art.
[0050] The polymeric delivery materials of the present invention
can optionally be labeled with any of a wide variety of agents,
which are known to those skilled in the art. As examples, dyes,
fluorophores, chemiluminescent agents, isotopes, metal atoms or
clusters, radionuclides, enzymes, antibodies, or tight-binding
partners such as biotin and avidin can all be used to label the
polymeric drug-delivery composition for detection, localization,
imaging, or any other analytical or medical purpose. The polymeric
delivery composition, particularly the polymer of the matrix, can
also optionally be coated or conjugated with a wide variety of
molecules in order to modify its function, improve its stability,
or further modify the rate of release of the API. As examples, the
drug-delivery composition can be coated with a covalently- or
non-covalently-attached layer of a species such as small molecules,
hormones, peptides, proteins, phospholipids, polysaccharides,
mucins, or biocompatible polymers such polyethylene glycol (PEG),
dextran, or any of a number of comparable materials. The wide range
of materials, which can be used in this fashion, and the methods
for accomplishing these processes, are well known to those skilled
in the art.
[0051] It will also be apparent to one skilled in the art that the
various starting components such as the polymer powder and the API
can be further manipulated and processed using a wide variety of
methods, processes, and equipment familiar to one skilled in the
art. For example, the dry components can be thoroughly mixed using
any of a number of known methods and equipments, such as
trituration with a mortar and pestle or blending in a
Patterson-Kelley twin-shell blender, before the initiation of the
wetting stage. Further a wide variety of shapes, sizes,
morphologies, and surface compositions of the drug-delivery
composition can be formed. For example, micro-particles or
cylindrical bodies with different aspect ratios can be prepared by
means of mechanical milling, molding, extruding or similar
processes of the paste-like or semi-solid or even solid wet
polymeric material. The resulting particles can be further treated
to prepare them for specific applications such as e.g. drug
delivery systems. As another example, the polymeric particles and
bodies can be immersed into oil such as plant oil for conservation
and storage. As yet another example, transforming the wetted
mixture, paste or dough into micro-particles or polymeric bodies by
means of processes such as drying, rheological methods, grinding,
milling, pressure homogenization, molding, and/or other such
well-established procedures can yield a wide range of final
products. As another example, the polymeric drug-delivery
composition can be squeezed through a sieving disk containing
predefined pores or channels with uniform pore geometry and
diameter by an extrusion process, e.g. in a repeating manner.
[0052] According to an embodiment, the paste-like or semi-solid
mixture drug-delivery composition has a modulus of elasticity of at
least 10.sup.-4 Nmm.sup.-2. According to an embodiment, the
paste-like or semi-solid mixture drug-delivery composition has a
modulus of elasticity of at least 10.sup.-3 Nmm.sup.-2, and
particularly 10.sup.-2 Nmm.sup.-2, and more particularly 10.sup.-1
Nmm.sup.-2.
[0053] According to an embodiment, the paste-like or semi-solid
mixture has a viscosity of not more than 500 Pas, and particularly
of not more than 300 Pas. According to an embodiment, the
paste-like or semi-solid mixtures has a viscosity of not less than
few mPas, for example 100 mPas, and particularly of not less than 1
Pas.
[0054] According to an embodiment, the pharmaceutical active
compound is provided as powder containing particles ranging from
about 100 nm to about 50 .mu.m, particularly from about 500 nm to
about 30 .mu.m, and more particularly from about 1 .mu.m to about
10 .mu.m.
[0055] FIG. 1 illustrates processing steps of a manufacturing
method according to an embodiment. An aspect of this embodiment is
that the overall amount of water added is deficient with respect to
dissolution of the excipients. First, the dry polymer powder is
mixed together with the API, for example, antibodies. In a further
process, this dry mixture is gradually wetted and mechanically
worked to obtain a paste. It should be noted that the aqueous
solution is gradually added to the dry mixture different to other
approaches, which gradually add a dry powder to a solution. In
further processes, the paste can be further processed to obtain
particles of a given size, shape and size distribution. In further
processes, the thus formed particles can be dried, for example by
freeze-drying.
[0056] FIG. 2 illustrates processing steps of a manufacturing
method according to an embodiment. The aspect of this embodiment is
that the overall amount of water added is deficient with respect to
dissolution of the excipients. The particle formation via quasi-dry
conditions in grinding and milling processes are embodiments of the
mechanical procedures such as algorithmic cycles of pressing and
folding/mixing.
[0057] Similar to the embodiment of FIG. 1, a dry powder is
prepared by mixing with a subsequent wetting of the same. In
further processes, mechanical working such as grinding or milling
is used to form particles from the wetted composition, which
exhibit solid-like properties. In further processes, the surface of
the particles is modified to further alter the release
characteristics. In further processes, the solution added to the
mixture is removed.
[0058] In the following, specific examples are described.
Example 1
[0059] Dry gelatin (10 g) is mixed with small aliquots (1 g) of
water in a series of consecutive steps under steady kneading up to
a gelatin-to-water ratio of 2. Continuous kneading/mixing for 3
minutes leads to a single gelatin body of well-defined elasticity
but only small plasticity. The introduction of this gelatin body
into water at room temperature results in a stable, gelatinous
body, which does not swell significantly over a period of days and
weeks (cp. FIG. 3).
Example 2
[0060] Dry gelatin (10 g) is mixed with 5 g of water. In contrast
to the preparation process of FIG. 3 the mechanical kneading was
carried out for a time period of 10 seconds only. The obtained
gelatin body is presented in FIG. 4a right after formulation. The
total disintegration of the gelatin body ten hours after
formulation is given in FIG. 4b. The water of the beaker is
starting to gel and forms a continuous gelatinous body about 30
hours after formulation.
Example 3
[0061] 5 ml of water was added to a mixture of 5 g of
carboxymethylcellulose and 5 g of chitosan. This mixture was
mechanically kneaded for 3 minutes and the solid body demonstrated
in FIG. 5 (a) was formed and suspended in water at room
temperature. This same system was photographed after predefined
periods of time as presented in FIGS. 5 (b) to (h). A continuous
swelling process is observed during the first documentation period
of 42 hours, however, not leading to disintegration of the solid
mass. Disintegration was observed with a 10 second treatment of the
same composition (not shown) as observed in the gelatin system of
Example 2 (FIG. 4). Further observation of the mechanically treated
composition up to 145 hours after preparation demonstrates an
increasing tendency of disintegration. The stabilization effect via
the mechanical treatment is clearly visible during the first 42
hours; however, it is much less expressed as compared to the
gelatin composition as presented in FIG. 3.
Example 4
[0062] Equal amounts of dry carboxymethylcellulose and dry chitosan
(5 g each) are mixed with 5 g of acetic acid (pH 3) and a small
amount (less than 1 g) of plant oil. The mixture is mechanically
treated for 3 minutes and formed into a spherical body. It is
suspended into water at room temperature (FIG. 6a) and observed
over time (FIG. 6b, after 4 hours). Despite a clearly visible
swelling there is no disintegration during the 27 hours observation
period (FIG. 6c). The CMC/chitosan system is much less stable than
the gelatin system (EXAMPLE 1). If the system is mechanically
treated for only 10 seconds the disintegration of the spherical
body after suspension into water at room temperature is starting
more or less directly (not shown) and its behavior is, at least in
principle, comparable to the gelatin system of EXAMPLE 2. The
gelatin system shows a little more stability.
Example 5
[0063] First, a calcium alginate film was prepared by addition of a
calcium chloride solution to 1.0 g aqueous alginate gel (2%, 0.01%
sodium azide) in a flat bowl. After 10 minutes the resulting film
was separated from mold and dried for 2 minutes on white filter
paper. Second, 2 mg of antibody 1 of the type of gamma globulin was
placed onto the centre of the film. Third, the film was folded
together and kneaded by hand for 7 minutes forming ultimately a
spherical particle. To this particle, 1.0 g of an isotonic sodium
chloride solution was added. The release of antibody 1 was
determined spectroscopically by the UV 280 nm method under sink
conditions (cp. FIG. 7, Example 5). Ultimately we observed a very
slow release rate (18.5% after 8.5 weeks).
Example 6
[0064] First, a calcium alginate film was prepared by addition of a
calcium chloride solution to 1.0 g aqueous alginate gel (2%, 0.01%
sodium azide) in a flat bowl. After 10 minutes the resulting film
was separated from the mold and dried for 2 minutes on white filter
paper. Second, 25 mg of micro-crystalline cellulose and 50 mg of an
aqueous antibody 2 (of the gamma globulin type) solution was placed
onto the center of the film. Third, the film was folded together
and kneaded by hand for 7 minutes forming ultimately a spherical
particle. To this particle 1.2 g of an isotonic sodium chloride
solution was added. The release of antibody 2 was determined
spectroscopically by the UV 280 nm method under sink conditions
(cp. FIG. 7, Example 6). Ultimately we observed a medium release
rate of 46% in 9.7 weeks. After 3.7 weeks about 90% of released
antibody 2 is active.
Example 7
[0065] 66 mg of an antibody 2 solution (25 mg/ml) was added to 24
mg of micro-crystalline cellulose and 90 mg of castor oil. This
mixture was mechanically treated using a glass rod for 1 minute.
The resulting product was mixed with 1.5 g of an aqueous alginate
gel (2%, 0.01% sodium azide) and then dropped into a cold aqueous
calcium chloride solution (18%) under stirring (magnetic stirrer
500 U/min). The obtained capsules were separated from suspension
and washed two times with double distilled water. The resulting
alginate capsules were added to 3.0 g of an isotonic sodium
chloride solution (0.01% azide). The release of antibody 2 was
determined spectroscopically by the UV 280 nm method under no-sink
conditions (cp. FIG. 7, Example 7). This system represents a mixed
hydrophilic/hydrophobic system. The resulting release behavior is
demonstrating a two-phase characteristic; after a fast release
period of 73% in 2.7 weeks there is a slowing down to another 14%
over the next 22 weeks. After 25 weeks of release about 93% or the
released antibody 2 is bio-active as checked by ELISA.
Example 8
[0066] 200 mg of an antibody 3 (of gamma globulin type) solution
(50 mg/ml) was added to 80 mg micro-crystalline cellulose and 90 mg
of castor oil. This mixture was mechanically treated using a glass
rod for 1 minute. The resulting product was mixed with 1.0 g of an
aqueous alginate gel (2%) and then dropped into a cold aqueous
calcium chloride solution (18%) under stirring (magnetic stirrer
500 U/min). The obtained capsules were separated from suspension
and washed two times with double distilled water and finally added
to 5.0 g of an isotonic sodium chloride solution. The release of
antibody 3 was determined spectroscopically by the UV 280 nm method
under no-sink conditions (cp. FIG. 7, Example 8). Ultimately, we
observed a similar behavior as in previous EXAMPLE 7. After about 4
weeks of release about 90% of the released antibody 3 is bio-active
as determined by ELISA.
* * * * *